The engagement of neuronal chemokine receptors by progeny HIV-1 will be investigate as to its relevance in HIV-1 neuropathogenesis. The hypothesis proposed is that virion binding to chemokine receptors induces activation of neuronal signaling pathways leading to cell death. We suggest that neuronal injury facilitates further compromise of where neuronal injury facilitates, in paracrine fashion, further demise through the recruitment and activation of brain mononuclear phagocytes (MP) to areas of brain tissue damage. This idea is based on data accumulated by our group and other demonstrating expression or functional chemokine receptors on neural cells. HIV-1 may itself bind to chemokine receptors expressed on neurons, astrocytes and/or microglia and alter intracellular signaling events without infection. This event may lead to neuronal dysfunction and ultimately apoptosis. To determine whether or not neuronal signaling and apoptosis are linked, we will study the extent to which virion-associated HIV-1 enveloped HIV-1 envelope glycoprotein (HIV-1 gp120) engages CXCR4 on neurons and induces intracellular signaling events leading to cell injury and apoptosis. The experiments will determine whether virus binding to CXCR4 is necessary and sufficient to induce phosphoinositide-3 kinase (PI3-kinase) activation. We will explore whether PI3-kinase activation and apoptosis signaling pathways, for examine those involving caspases, are linked to one another. The second part of this proposal will determine, and under what circumstances, neuronal chemokines are proposed are produced. Neuronal chemokines will be studied to determine whether they affect MP innate immunity and/or virion-neuronal interactions. These works will employ integrated initiatives in virology, immunology, receptor neuropharmacology and electrophysiology. The current proposal takes advantage of the unique training environment and the breadth of research expertise within the proposed Center. The collaboration between investigators in the Center for Viral Pathogenesis on the project and others will ensure that the work can be accomplished successfully in the designated time frame. Most importantly, the rich training environment and the broad technologies outlined will allow this and other applications within the CVP to flourish. The results obtained from these experiments could provide important avenues for developing novel therapeutic strategies to combat HAD as well as other neurodegenerative disorders.